What's Needed To Transform Clinical Trials In Early-Stage Prostate Cancer
By Paul Peter Tak, MD, Ph.D., FMedSci, president and chief executive officer, Candel Therapeutics
The clinical trial landscape in prostate cancer faces a critical challenge: how to better capture the patient experience while maintaining scientific rigor. Despite significant advances in cancer treatment overall, the approach to early-stage prostate cancer has remained largely unchanged for over three decades. This stagnation is particularly concerning given the projected doubling of global annual incidence from 1.4 million cases in 2020 to 2.9 million by 2040.1 As clinical development professionals, we must critically examine our traditional trial methodologies and embrace innovative approaches that better serve this growing patient population.
My experience as both a physician and patient has taught me that the most valuable insights often come not from data alone but from truly listening to our patients. This dual perspective informs my approach to clinical trial design and has been profoundly shaped by my own experience as a previous patient with cluster headaches, a condition so painful it's known among neurologists as "suicide headache." Through those years of living with debilitating pain, I learned the critical importance of understanding the patient experience and the benefit of having this understanding inform clinical trials.
The Case For Change
Clinical trials in prostate cancer face unique challenges due to the disease’s long-term progression. Traditional trial designs, focused primarily on survival endpoints, often require extended follow-up periods and large patient populations to demonstrate statistical significance. In the case of prostate cancer, this poses many challenges in better understanding the disease and best treatment options. While survival metrics remain essential, this narrow focus has inadvertently created barriers to innovation and potentially limited opportunities to develop interventions that could meaningfully benefit patients before their disease advances.
The limitations of current trial designs are, for example, evident in low-risk prostate cancer management. Active surveillance has emerged as a standard strategy to avoid or delay the side effects of radical therapy in patients with low- to intermediate-risk prostate cancer. However, data shows that 34.3% of patients on active surveillance reported anxiety.2 Among those receiving radical therapy after subsequent progression, a significant number report treatment-related complications that significantly impact daily life, including urinary incontinence, erectile dysfunction, and psychological effects.3 Therefore, in this population, there is a need for a new treatment that is well tolerated and that may stop the progression of the disease (progression-free survival), avoiding or delaying the need to undergo radical prostatectomy or radiotherapy over time.
Survival Is Not The Whole Story
Similarly, previous clinical trial designs for patients with intermediate- to high-risk disease who will receive standard-of-care radical therapy have not adequately captured the full impact of the patients' experience. While we focus on survival, we often undervalue the profound effects of local or metastatic disease progression and the need for additional treatment, such as androgen-deprivation therapy, associated with significant side effects and loss of quality of life.
Therefore, it is important to look beyond survival rates. Comprehensive assessment of the patient experience must include important aspects of daily life affected by disease progression or hormonal therapy, such as urinary symptoms, intimacy with partners, bone pain, fatigue, hot flashes, loss of muscle mass and strength, and emotional well-being. Therefore, in this population, there is a need for a new treatment that will help increase the percentage of patients who will be cured after treatment (disease-free survival). Evidence based on the experience in other forms of cancer supports expanding trial endpoints beyond survival metrics. A clinical study on the benefit of early palliative care for patients with metastatic non-small cell lung cancer demonstrates the value of this approach: patients who received early palliative care with their standard oncology care not only survived longer (11.6 months vs. 8.9 months) but also demonstrated much lower levels of depression (16% vs. 38%) and overall higher quality of life when compared to those who received just standard oncology care.4 This underscores the importance of understanding a patient’s emotional well-being as it relates to the quality of life and how understanding quality of life in a clinical trial setting can help better inform results.
Implementation
A more holistic view of what matters to patients with prostate cancer requires careful attention to defining the best endpoints in the clinical trials. Measurement of relevant biomarkers in peripheral blood, advanced imaging techniques, and serial prostate biopsies combined with capturing the patient experience should be integrated into trial protocols, as these are critical to evaluate progression-free survival and disease-free survival.
Site selection is crucial for success. Of importance, all centers routinely treating early, localized prostate cancer patients already can perform intra-prostate administration of investigational medicines and evaluate disease progression after follow-up. Therefore, such clinical trials are not limited to academic centers but also can be conducted in community centers after adequate training on the protocol.
Best Practices
The implementation of progression-free survival and disease-free survival endpoints is aligned with current clinical care. Sites currently treating localized prostate cancer patients already have the infrastructure for monitoring disease progression through imaging studies and serial biopsies. In clinical trials, these processes need to be standardized and validated at selected sites.
In clinical trials of intra-prostatic investigational medicines, key elements include establishing protocols for intra-prostatic administration and standardized procedures for monitoring disease progression. Sites need to maintain consistent monitoring protocols and clear communication channels between care teams to achieve optimal data quality and patient retention.
Technology infrastructure supports successful implementation. Electronic data collection systems can integrate with existing medical records while maintaining ease of use. Technical support helps ensure data integrity and smooth site operations.
Patient engagement also plays an important role. Support staff need to guide patients through the trial process, particularly around procedures like serial biopsies and imaging studies. Regular monitoring helps identify potential progression, supporting both endpoint measurement and patient care.
Looking ahead, emerging technologies may enhance the detection of disease progression. Integration of advanced imaging and biomarker analysis could provide earlier indicators of treatment response and potential tumor recurrence. These advances warrant evaluation for both scientific validity and practical implementation within community treatment centers.
Future Impact
Focusing on progression-free survival and disease-free survival as primary endpoints in clinical trials in patients with prostate cancer benefits all stakeholders. Most notably, developing medicines that positively impact these endpoints can provide patients with a greater benefit than just overall survival. Additionally, implementing these endpoints in clinical trials can lead to shorter trial durations for industry sponsors, compared to solely focusing on overall survival, which requires lengthy follow-up. Furthermore, the introduction of new medicines that not only improve overall survival over 10 years but also halt tumor progression or cure the disease will expand the treatment options available to physicians.
To make progress, coordination is key. Regulatory bodies should guide the use of optimal endpoints in clinical trials, while industry sponsors should prioritize endpoints that truly matter to patients. It is crucial to involve payors early in the development process. The goal is to provide new treatments for patients with unmet needs.
The evolution of prostate cancer trials is timely, given the growing global burden of this disease. While survival rates for advanced disease have improved, there is still room for improvement in disease outcomes in patients with localized, non-metastatic disease.
References:
- The Lancet Commission on Prostate Cancer, Prostate cancer cases expected to double worldwide between 2020 and 2040, new analysis suggests ' (Media Release, 4 April 2024).
- Sypre D, et al. Impact of active surveillance for prostate cancer on the risk of depression and anxiety. Sci Rep. 2022 Jul 28;12(1):12889.
- Corsini C, et al. Patient-reported Side Effects 1 Year After Radical Prostatectomy or Radiotherapy for Prostate Cancer: A Register-based Nationwide Study. Eur Urol Oncol. 2024 Jun;7(3):605-613.
- Temel JS, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med 2010;363:733–742.
About The Author:
Paul Peter Tak, MD, Ph.D., FMedSci, is the president and chief executive officer of Candel Therapeutics since September 2020, overseeing its IPO on Nasdaq in 2021. He received his medical degree cum laude from Amsterdam University Medical Center and his Ph.D. and specialty training from Leiden University Medical Center. Dr. Tak has held positions including associate clinical professor of medicine at UCSD School of Medicine, professor of medicine and chair of the Department of Clinical Immunology and Rheumatology at Amsterdam University Medical Center, and honorary senior visiting fellow at University of Cambridge. At GlaxoSmithKline, he served as senior vice president, chief immunology officer, and global development leader. He has authored more than 600 peer-reviewed publications and is a fellow of the Academy of Medical Sciences. Currently, he serves on the boards of Sitryx Therapeutics (cofounder), Levicept, and Citryll, as chair of the board.